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\begin{document}

\title{A report of QTc prolongation in a massive multi-drug overdose involved
Nortriptyline and Livergol}



\author[1]{Somayeh Gharibi}%
\author[2]{Hanieh Salmani izadi}%
\author[1]{Hadi  Jafari}%
\affil[1]{Mashhad University of Medical Sciences Emam Reza Hospital}%
\affil[2]{Mashhad University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
We report the case of a massive Nortriptyline and Livergol overdose,
presenting with the typical Nortriptyline intoxication features,
including QT prolongation and rapid response to the treatment, which
provides a rationale for the safety profile of Silymarin medications
with minimal risks of drug-drug interactions.%
\end{abstract}%



\sloppy


\textbf{A report of QTc prolongation in a massivemulti-drug overdose
involved Nortriptyline and Livergol}

Somayeh Gharibi\textsuperscript{1*}, Hanieh Salmani
izadi\textsuperscript{2},

Medical Toxicology research center, School of medicine, Mashhad
University of Medical Sciences, Mashhad, Iran.

Student Research Committee, Mashhad University of Medical Sciences,
Mashhad, Iran.

\textbf{Abstract}

We report the case of a massive Nortriptyline and Livergol overdose,
presenting with the typical Nortriptyline intoxication features,
including QT prolongation and rapid response to the treatment, which
provides a rationale for the safety profile of Silymarin medications
with minimal risks of drug-drug interactions.

\textbf{key clinical message}

As the interests in the use of herbal medicine like Livergol in the
treatment of liver diseases, increases, there is a growing need to
ensure its safety. This report highlights the good safety profile of
Livergol with no considerable interaction between Nortriptyline and
Livergol, associated with complicated Tricyclic-anti-depressants
overdose treatment.

\textbf{Keywords} : Tricyclic antidepressants, intoxication,
nortriptyline, Silymarin, Livergol, QTc prolongation

\textbf{Introduction}

Tricyclic antidepressant (TCA) poisoning, including nortriptyline (NT)
and amitriptyline, is among the highly prevalent toxicities. They are
second-line drugs next to Selective serotonin reuptake inhibitors
(SSRIs) in the management of depression. They carry a higher case
fatality, of 7.1\% deaths per overdose, with more toxic effects than
most other antidepressants {[}1{]}. Despite the potentially dangerous
toxicity of TCAs, they remained commonly prescribed for various forms of
depression, anxiety conditions, and chronic neuropathic pains. Common
adverse effects of TCA therapy include blurred vision, dry mouth,
tachycardia, orthostatic hypotension, cardiac arrhythmia, sedation,
constipation, and urinary retention {[}2{]}.

Silymarin with the trade name of Livergol\selectlanguage{ngerman}® is a Silybum marianum seed
derivative with antioxidant properties. Silymarin has been highlighted
because of its various biological activities such as immune modulator,
hypolipidemic, anti-depressant, antifibrotic, anti-inflammatory,
sedative, and antitumor properties. Additionally, it is widely used for
its well-known hepatoprotective effect. There are very limited reports
on the toxicity of silymarin in human studies, so this substance is
accepted as a safe herbal product. The most common adverse effects
reported on its use include gastrointestinal symptoms, headaches, and
dermatological reactions, but little is known about its potential for
drug interaction {[}3, 4{]}.

\textbf{Reason for report}

Considering cardiovascular toxicity as the major dangerous toxicological
concern in nortriptyline poisoning, and its possible drug interaction
with Livergol when co-administrated, here we report serial ECG changes
and QTc prolongation in a multi-Drug Overdose Involving nortriptyline
and Livergol.

\textbf{Case presentation}

A 41-year-old woman was presented to the local emergency department
(ED), in Torbat-e Heydariyeh, via Emergency Medical Services with
altered mental status, following a suicide attempt with Tricyclic
Antidepressant. Her prehospital vital signs included: a temperature of
37 °C, a pulse rate of 86/minute, respiratory rate of 16/minute, and
blood pressure of 110/70 mm Hg. The patient was unconscious, drowsy, and
assessed with a Glasgow Coma Scale (GCS) of 13 out of 15. Gastric lavage
was promptly performed and then she was transferred to the referral
center for further evaluation.

She was admitted to the inpatient poisoning care of Emam Reza hospital
of Mashhad, the next morning. Upon arrival, the patient was non-vocal
and unresponsive to the pain. The GCS was estimated at 9-10/15. vital
signs and other physical examinations showed acceptable general
condition. Normal breath sounds with no rales or murmur were observed.
Her medical history was significant for diabetes, ischemic heart
disease, and depression. Medications available to the patient included
Nortriptyline, Metformin, Livergol, Gabapentin, and Thiamine supplement.
She had taken metformin for treatment of her diabetes for years. Upon
questioning, it was claimed that she had taken large but uncertain
quantities of Nortriptyline, Livergol, Gabapentin, and Thiamine, about
50 pills in total. Social history was positive for waterpipe tobacco
smoking.

Due to the patient history mentioned above, we ran a full blood and
urine analysis which was positive for TCAs. An ECG on presentation
demonstrated a QTc interval of 481 milliseconds at 10 AM (Figure 1). The
patient was treated with a vial of bicarbonate and 10 ccs of potassium
chloride, intravenous (I.V). the subsequent ECG, at 4 PM, demonstrated
QTc shortening to 463 milliseconds (Figure 2). Blood glucose control was
managed according to the insulin therapy protocol. ECG, Arterial blood
gases (ABG), and urinary output were regularly checked. During this
time, she remained hemodynamically stable, and no other abnormality was
noted on the serial ECG. She also received I.V pantoprazole (40 mg), and
serum therapy had been ongoing since her early admission. A psychiatry
consult was ordered to assess suicidal ideation in the context of TCA
overdose.

on the evening of the same day, the patient wished for her discharge
against the medical advice. The possible risks of an early
self-discharge against the medical advice, including; cardiac arrhythmia
and heart arrest were explained to her. Even with this explanation, the
patient remained intensified with her decision and immediately started
the process and got discharged at 5 PM. But on a further phone call
follow-up in the next month, the patient was fine with no complications
and reported full remission of all symptoms.

\textbf{Discussion}

We report the case of a multiple drug overdose involving Nortriptyline,
Livergol, Gabapentin, and Thiamine supplement, which resulted in a QTc
interval prolongation presented on ECG on arrival. According to the 2020
Annual Report of the American Association of Poison Control Centers'
National Poison Data System, antidepressants are reported among the top
5 substance classes most frequently involved in toxic exposures, and
over the past 10 years, their exposure has increased most rapidly and
with more serious outcomes, by 5.84\% per year or 1,793 cases per year
{[}5{]}. As a class, TCAs are categorized in the top 25 classes
associated with the greatest fatality {[}6{]}.

Delayed clinical deterioration or even death following a relative
stabilization or improvement, days after the ingestion had been
previously documented. A previous case, reports a 61-year-old man
presenting after an nortriptyline overdose up to 2500 mg, with QRS
widening to 240 milliseconds despite the further narrowing of QRS
interval, his course got complicated by repeated episodes of wide
complex tachycardia and required continuous sodium bicarbonate treatment
until day 14 hospitalization {[}7{]}. In another case of a patient with
an initial nortriptyline level of 1518 mg/L and episodes of generalized
tonic-clonic seizures, sodium bicarbonate infusion was administrated for
a total of 5 days {[}8{]}. however, in all of these cases, significant
initial toxicity was observed. Our patient with large ingestion of
Nortriptyline still showed no delayed deterioration and responded very
well on a short (12 hours) sodium bicarbonate treatment course. In line
with the result of our case, in a report by Pierog and colleagues,
despite a large amount of amitriptyline ingested, the patient only
received therapy for 48 hours {[}9{]}.

The recommended therapeutic window of NT is defined between 50 ng/mL and
150 ng/mL. Normally, medications with NT start at a low dose, and then
gradually increased to reach the optimal therapeutic level. However, the
plasma steady-state concentrations of TCAs in the course of treatment
vary interindividual, as the therapeutic or toxic concentrations are
mostly determined by NT metabolism and clearance rate. But, in general,
plasma levels above 150 ng/mL are associated with the incidence of
adverse effects {[}10{]}. Given that, conventional dosage regimen can
lead to toxic concentration in slow metabolizer individuals, as Lee et
al. reported a case presenting with adverse effects such as dizziness,
dry mouth, and constipation after 6 days prescription of routine dosage
of NT {[}11{]}. Drug interactions leading to the decreased metabolism
rate can be observed in treatment with two or more CYP enzyme
metabolizers, resulting in enzyme competition. Shim et al. reported
increased blood levels of TCA in schizophrenic patients under treatment
of paroxetine, a potent CYP2D6 inhibitor {[}12{]}.

Several successful studies have been evaluating silymarin's benefits as
an anti-inflammatory, anti-diabetic, anti-Alzheimer, and anticancer
agent. Due to the extensive therapeutic roles of Livergol in human
studies and its wide use in liver diseases, its safety is very important
and should be prescribed with caution, especially when co-administered
with drugs that carry a narrow therapeutic window. According to
pharmacological studies, silymarin was safe at therapeutic doses in
humans, only transient side effects like GI discomfort were reported.
Silymarin has shown limited effect on the pharmacokinetics of some drugs
in vivo; inhibitory effect on cytochrome P-450 enzymes could affect
warfarin metabolism. Though it did not have a major effect on drug
metabolism, it is suggested that their combination should be used with
caution. In total, Livergol has a good safety profile and is well
tolerated even at high doses {[}3, 13{]}.

One major cause of concern in the use of herbal medicine is that they
mainly contain physiochemical constituents that may interact with
prescription drugs. Regarding the little information available about
herbal product potential for drug interaction and pharmacokinetic
alternation, healthcare practitioners usually take caution against
co-administration of Livergol and pharmaceutical drugs to avoid any
possible clinically significant interactions {[}14{]}.

\textbf{Outcome}

In our case, a suicidal attempt with massive multi-drug ingestion of
Nortriptyline and Livergol, the patient presented with the typical
Nortriptyline intoxication presentation, including QT prolongation, and
rapid response to the treatment, as discussed above. Despite the large
amount of Livergol ingested, no significant GI upset or any symptoms
associated with Livergol poisoning were observed, which highlights the
good safety profile of the Silymarin products like Livergol. There were
also no adverse drug-drug interactions observed in co-admiration of
these two drugs.

\textbf{Conclusion}

To the best of our knowledge, a high dose of Livergol can be
well-tolerated, and only some transient side effects like allergic
reactions, itching, headache, and GI disturbance are sometimes
presented. According to the data of our case, there is also no
considerable interaction between Nortriptyline and Silymarin products,
associated with complicated TCA overdose or treatment.

\textbf{Acknowledgment}

All authors are deeply thankful to the physicians, nurses, and other
allied health care workers who were responsible for the care of this
patient.

\textbf{Conflicts of Interest}

No conflict of interest or extra\selectlanguage{english}-institutional commercial funding exists
for any of the authors associated with the manuscript.

I declare that ``none'' of the authors listed in the manuscript are
employed or represented by the agency related to the government of the
Islamic Republic of Iran. there are no benefits or connections to the
government of the Islamic Republic of Iran.

\textbf{Informed consent}

Written informed consent from the patient was also obtained.

\textbf{Author contributions}

Somayeh Gharibi: Conceptualization, Supervision, writing the original
draft and editing

Hanieh Salmani izadi: Data collection, writing the original draft, and
writing review and editing

\textbf{References}

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3. Soleimani, V., et al., Safety and toxicity of silymarin, the major
constituent of milk thistle extract: An updated review. Phytother Res,
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4. Hadi, A., et al., The effects of silymarin supplementation on
metabolic status and oxidative stress in patients with type 2 diabetes
mellitus: A systematic review and meta-analysis of clinical trials.
Complement Ther Med, 2018. \textbf{41} : p. 311-319.

5. Gummin, D.D., et al., 2020 Annual Report of the American Association
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6. Gummin, D.D., et al., 2017 Annual Report of the American Association
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11. Lee, S.Y., et al., A case report of a poor metabolizer of CYP2D6
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Med Sci, 2004. \textbf{19} (5): p. 750-2.

12. Shim JC, G.B., Park JH, Yoon YR, Sin JG, Kim JI, Ahn DS, Kim YK, Cha
IJ, Kim YH., Combined therapy of paroxetine and tricyclic antidepressant
in depression of schizophrenic patients. Korean Neuropsychiatr Assoc,
1997. \textbf{36} .

13. Karimi, G., et al., ''Silymarin'', a promising pharmacological agent
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14. Wu, J.-W., L.-C. Lin, and T.-H. Tsai, Drug--drug interactions of
silymarin on the perspective of pharmacokinetics. Journal of
Ethnopharmacology, 2009. \textbf{121} (2): p. 185-193.

\textbf{Figures}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

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Figure 1: The initial electrocardiogram of a 51-year-old female patient
with nortriptyline overdose shows a QTc interval of 481 milliseconds\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2: The subsequent electrocardiogram of the same patient after
initiation of the therapy, reveals QTc shortening to 463 milliseconds\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure/Figure}

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